Derivatives of dibenzo(a,b)5h-cycloheptene,method of preparation,and application thereof

ABSTRACT

NEW CHEMICAL COMPOUNDS OF THE FORMULA   FORMS PARTS OF A HETEROCYCLE; AND ACID ADDITION SALTS THEREOF. THESE COMPOUNDS ARE ACTIVE ON THE CENTRAL NERVOUS SYSTEM AND ON THE CARDIOVASCULAR SYSTEM.   R1-N(-R2)- 5-(R1-N(-R2)-CH2-C=C-CH=)-5H-DIBENZO(A,D)CYCLOHEPTENE WHEREIN R1 AND R2 ARE EACH SELECTED FROM THE GROUP CONSISTING OF ALKYL OR HYDROXYALKYL, OR WHERE

United States Patent Ofice 3,819,723 Patented June 25, 1974 Int. Cl.C07c 33/06 US. Cl. 260-618 R 2 Claims ABSTRACT OF THE DISCLOSURE Newchemical compounds of the formula wherein R and R are each selected fromthe group consisting of alkyl or hydroxyalkyl, or where forms part of aheterocycle; and acid addition salts thereof. These compounds are activeon the central nervous system and on the cardiovascular system.

the forlnulawherein R and R are each selected from the group whichconsists of alkyl or hydroxyalkyl or wherein forms part of aheterocycle.

The alkyl "radicals as well as the alkyl moieties of the hydroxyalkylradicals, represented by R and/or R are preferably lower alkyl radicals.

When R and/or R represent hydroxyalkyl radicals this may advantageouslybe an w-hydroxyalkyl radical,

notably fl-hydroxyethyl.

. The heterocyclic radical of which may constitute a portion ispreferably a heterocycle of from four to seven members. Thus, thisheterocycle may be pyrrolidine, piperidine, morpholine, perhydroazepineor a N-alkyl piperazine, of which the alkyl is preferably lower alkyl.

Since these new chemical compounds of the formula given above can formacid addition salts with acids, these acid addition salts alsopossessing therapeutic properties, these acid addition salts are equallyincluded as part of our invention.

In preparing these new chemical compounds we prefer to eifectcondensation between a propargyl metal halide of the formula wherein Xis a halogen; M is a metal; and n is equal to the valence of M, and thecompound 5-oXo-dibenzo[a,d] cycloheptene. The resulting compound issubjected to a Mannich reaction utilizing a source of formaldehyde andan amine of formula R1 HN/ R and R having the significance aboveindicated.

The starting material 5-oxo-dibenzo[a,d]cycloheptene may be prepared inaccordance with procedures described in Cesk. Farm, Volume 11, pages 3to 7 (1962), or in accordance with procedure described in Journ. Med.Chem., Volume 8 (6), page 886 (1965).

Starting with this compound 5-oXo-dibenzo[a,d]cycloheptene, our novel,chemical compounds may be prepared in accordance with two variantprocesses which may be illustrated as follows:

YI-CECH HO CH CEGH CH: 0 CH; O

aknogo-cnlx, M amaze-cam, M) )0,

(I) (IV) The central compound on this flow sheet is the startingmaterial S-oxo-dibenzo [a,d]cycloheptene of formulabenzo[a,d]-H-cycloheptene. This is a new chemical compound. We mayadvantageously carry out this first step of the process, the a stage, byutilizing propargyl aluminum bromide as reagent.

In the second stage of the process, marked a on the flow sheet, aMannich reaction is carried out on 5-(2- propyn- 1 -ylidene dibenzo[a,d] -5H-cycloheptene.

In order to effect this reaction, compound II is treated, preferably atthe boiling point, in a mixture of ethanol and a solvent which increasesthe reaction velocity, such as a cyclic ether oxide, for example dioxaneor tetrahydrofuran, with a suitable amine and a source of formaldehyde.The reaction is preferably carried out in the presence of catalyticamounts of a copper compound. For this purpose there may be used saltsand oxides of copper, for example cupric acetate, basic cupric acetate,cupric bromide, cupric chloride, cupric ammonium chloride, cupricformate, cupric nitrate, cupric oxide, cupric sulfate, cupric p-toluenesulfonate, cuprous acetate, cuprous bromide, cuprous chloride, cuprouscyanide, cuprous iodide, cuprous oxide, cuprous thiocyanate, and othercopper compounds.

In the second disclosed process for preparing our newdibenzo[a,d]-5H-cycloheptene derivatives, which is illustrated at therighthand side of the flow sheet, 5-oxo-dibenzo[a,d]cycloheptene iscondensed with about two equivalents of a propargyl metal halide tosecure compound III, the new chemical compound 5-(2-propyne)-5-hydroxy-dibenzo[a,d]-5H-cycloheptene. This step is indicated as b on theflow sheet. We prefer to use in this stage propargyl magnesium bromideor propargyl aluminum bromide.

A Mannich reaction, denominated b on the flow sheet, is then carried outon compound 111 under conditions similar to those of the correspondingstage a in the first variation of our process. There is thereby securedthe new S-hydroxy compound, IV, which, by dehydration (step b yields thedesired pharmacologically active compounds I. This dehydration can becarried out in a strongly acid medium, preferably in the presence ofsulfuric acid. The use of hydrochloric acid results, in certain cases,in an addition reaction on the triple bond, notably when is derived frompiperidine, perhydroazepine, morpholine, an N-alkylpiperazine or when Ror R are ethyl radicals.

Our new chemical compounds of formula I have pharmacological propertieswhich make them valuable in therapy. In particular, they are active onthe central nervous system and in the cardiovascular system. Their acidaddititon salts, especially those with pharmacologically acceptableacids, possess the same therapeutic properties as the bases, and areuseful as therapeutic agents. Among such salts may be mentioned theoxalates, maleates and hydrochlorides.

Our invention is also directed to applications or uses of the newcompounds of formula I, as well as to pharmaceutical compositionscomprising a compound of formula I, or one of its non-toxic acidaddition salts, dispersed or distributed in a therapeuaticallyadministrable vehicle or excipient.

Our invention may be illustrated by the following examples.

EXAMPLE I 5#(2-Propyne-l-ylidene)dibenzo[a,d]-5H-Cycloheptene (Compound11) To 100 milliliters of a 1N solution of propargyl aluminum bromide inanhydrous ether there is added, drop by drop, a solution of 0.1 mol of5-oxo-dibenzo[a,d]cycloheptene in 80 milliliters of anhydroustetrahydrofuran while maintaining gentle boiling. Agitation is continuedfor 5 hours at room temperature. There is then added a mixture of water,ice and aluminum chloride and the reaction mixture is then extractedwith ether, dried over sodium sulfate, and the solvent removed byevaporation under vacuum.

The resulting product is then dissolved in a minimum amount ofchloroform and subjected to chromatography on basic alumina and theneluted with ether. The ether is removed from the resulting etherealsolution, followed by redissolving the product in a warm mixturecontaining equal parts of ethanol and isopropanol. The solution issubjected to treatment with animal charcoal and filtered. The product,the title compound, crystallizes slowly. It is removed by centrifugalaction and dried. Its melting point is C. (Kofler).

EXAMPLE III 5-(Z-Propyne)-5-hydroxy-dibenzo [a,d]-5'H-Cycloheptene(Compound In) To 200 milliliters of a 1N solution of propargyl aluminumbromide in anhydrous ether, there is added, drop by drop, a solution of0.1 mol of 5-oxo-dibenzo[a,d]cycloheptene in 80 milliliters of anhydroustetrahydrofuran while maintaining gentle boiling. At the conclusion ofthe heating, the solution is allowed to stand, with agitation, at roomtemperature for 30 minutes. It is then cooled and treated with a mixtureof water, ice and ammonium chloride. This is followed by extraction withether, drying over sodium sulfate and removal of the solvent under areduced pressure, less than atmospheric, i.e. under vacuum. Theabove-named product crystallizes from cyclohexane. The crystals have amelting point of 117 C.

EXAMPLE 'III 5-(4-Dimethylamino-Z-butyne)-5-hydroxy-dibenzo[a,d]-SH-cyclohexane (Compound IV) In this type formula for compound IV, ofwhich this is an example, R and R are both methyl.

To 0.12 mol of dimethylamine in 40% aqueous solution, sufficient aceticacid is added to adjust the pH to 5. There is then added 15 millilitersof formol (formaldehyde source) in 30% aqueous solution;

0.1 mol of propargyl alcohol (compound III);

250 milligrams of cuprous chloride;

milliliters of propionic acid;

50 milliliters of dioxane.

The mixture is refluxed for 3 hours. It is then diluted by addition of 5volumes of water. Sufficient ammonia is added to render the solutionalkaline in reaction. This is followed by extraction with ether, dryingover sodium sulfate, and removal of the solvent at a reduced pressureless than atmospheric, i.e. under vacuum. The title compound is obtainedupon crystallization from cyclohexane. Melting point, 138 C.

EXAMPLE IV 5-(4-Dimethylamino-Z-butyne-l-ylidene)dibenzo[a,d]-SH-Cycloheptene (Compound I) This compound is identified herein asAU-2176, and it is represented by formula I where R and R are eachmethyl.

0.1 mol of compound 'IV as in Example III is dissolved, with heating, ina mixture of ethanol, water and concentrated hydrochloric acid whichmixture comprises 200 milliliters of ethanol, 40 milliliters of waterand 30 milliliters of concentrated hydrochloric acid. The mixture isbrought to a temperature of 70 to 75 C. for 2 hours, diluted by theaddition of 5 volumes of water and rendered alkaline by the addition ofammonia. This is followed by extraction with ether, drying over sodiumsulfate and removal of the solvent by evaporation at a reduced pressure,less than atmospheric, i.e. under vacuum. The title compound wassecured. Its analysis was confirmed by analysis of the hydrochlorideandmaleate salts thereof. The hydrochloride salt meltedat 210 C. and themaleate salt meltedat 118 C. Analysis confirmed the, emipic formula C HClN for the hydrochloride salt of compound I and the empiric formula C HNO' forthe maleate salt of compound I. Both salts were soluble inisopropanol and could be crystallized from a solution thereof in thissolvent.

[EXAMPLE V 5-(4- Piperadino-2 butyne-1-ylidene)dibenzo [a,d] -5H-Cycloheptene (Compound ll) milliliters of formol (formaldehyde source)in 30% aqueous solution;

0.1 mol of compound II;

250 milliliters of cuprous chloride 150 milliliters of ethanol;

50 milliliters of dioxane.

The mixture is heated at reflux for 3 hours. It is then diluted by theaddition of 5 volumes of water, followed by the addition of an excess ofacetic acid. It is then brought up to a temperature of 70 to 75 C. for 3hours. It is then diluted by the addition of 5 volumes of water andalkalinized by the addition of ammonia. Extraction with ether, dryingover sodium sulfate and expulsion of the solvent by evaporation at apressure less than atmospheric (under vacuum) yields the productidentified in the title.

This new compound was characterized by its dimaleate salt, which issoluble in ethanol andhas a melting point of 176 C. Analysis confirmedthe empiric formula In Table I below there are set forth the meltingpoints of a certain number of specific compounds IV in the form of theirsalts and as free bases, in each instance after recrystallization fromthe solvent indicated.

TABLE I Crystallization MI. E solvent C.)

Oxalate... Isopropanol 188 Dnsopropylammo Maleate--. Isopropanol/ether144 d1 Isopropyl oxide. 116 Piper-idino do Isopropannl 91Perhydroazepino Oxalate .-d0 168 N-methylpiperazino BaseCyelohexanelheptane-. 127 Morpholino ..do Isopropanol/heptane-.-- 68Methyl-fl-hydroxy- -..do Ethyl acetate 145 ethylamino.

In Table 2 below there are set forth the melting points and the resultsof the analysis of a number of compounds I in the form of their salts orof their free bases after recrystallization from the solvent indicated.There was assigned to certain compounds a reference number comprisingthe letters AU followed by a four-figured numeral. extracted w1th etherand the aqueous phase is rendered These references appear in column 2 ofthe Table.

i i TABLE II 1 Analysis I Crystallization M.P.

1i. solvent 0.) M01. wt. for Cale. Found Diethylamino Isopron 141-2Cz7H27NO4 429.5 433.5 Diisopropylamino C25 27N 341.5 345.0 Methylhydroxy ethyl O alate. Ethanol 171-2 C24Hz3N05 504. 5 410. 0 PyrrolidinoOxalate AU-217 .dfl 168-70 C25H2aNO4 401.4 396.5 Perhydroazepino Oxalatedo 162 Cz7Hz1NO4 429.5 434.0 Morpholino Oxalate All-217 95% et 185Camelot 417.5 421.0

K Acidimetry in non-aqueous medium.

b Purification by chromatography over basic alumina, elution with ether.

0 Then 187.

alkaline by the addition of ammonia. This is followed by extraction withether, drying over sodium sulfate, and removal of the solvent byevaporation at a reduced pressure, less than atmospheric, i.e.'undervacuum. This resulted-in the title compound, whose oxalate salt meltedat 188 C. Dissolved in 95% ethanol, elemental analysis confirmed theempiric'formula C H NO of the general formula represents N-methylpiperazino. There is dissolved, under warm conditions. 0.1 mol ofcompound IV in which is derived from N-methylpiperazine in a mixture ofethanol, water and pure sulfuric acid. There were 200 milliliters ofethanol, 40 milliliters of water and 30 milliliters of sulfuric acid inthis mixture. The entire mixture is As stated above, the compounds offormula I have interesting pharmacological properties, being active onthe central nervous system and on the cardiovascular system. Theseproperties are demonstrated by the test results on animals reportedbelow.

Theactivity on the central nervous systemmanifested itself above all inanti-depressive action. Thus, the compound AU-2176 in the form of itshydrochloride salt gives positive responses in mice and rats in thespecific tests for anti-depressants.

Administration to mice and rats in dosages of 20 milligrams per kilogramof body weight intraperitoneally or orally opposes the ptosis broughtabout in these animals by the simultaneous administration to them ofreserpine in dosages of 2 milligrams per kilogram of body weightintraperitoneally. In a dosage of 10 milligrams per kilogram,intraperitoneally administered, it also opposes the ptosis caused by theadministration to them of tetrabenazine (dosage 40 milligrams perkilogram subcutaneously).

Furthermore, in the same way as the classic antidepressants, AU-2176administered orally at a dosage of 15 milligrams per kilogram of bodyweight prolongs the motor excitation caused in rats by amphetamine(administered at a dosage of 4 milligrams per kilogramintraperitoneally). Furthermore, AU-2176 (the hydrochloride salt)administered to rats and mice at dosages of milligrams per kilogram ofbody weight intraperitoneally, exerts an antinociceptive actionvis-a-vis a chemical stimulus: phenyl benzoouinone.

With respect to the cardiovascular system the compounds I exertanti-arrhythmic action as shown by the following tests:

1. The following chemical compounds: AU-2l7l, AU-2l72, AU-2173, andAU-2176, administered in dosages varying between 25 milligrams and 50milligrams of the compound per kilogram of body weight (calculated asbase) prevent in mice in vivo the cardiac fibrillation resulting fromchloroform syncope.

2. AU-2176 (the hydrochloride salt) at concentrations of 5X10 to gramexerts in vitro a guanidinelike action on the isolated auricle of theguinea pig or rabbit, which animals were electrically excited, andprolongation of the refractory period also is observed.

3. The products AU-2l71, AU-2172 and AU-2176 ad-.

ministered by perfusion in guinea pigs brought about brady-cardiawithout affecting the form of the electrocardiographic trace.

Furthermore, all of these compounds administered intravenously in ratsat dosages in the neighborhood of 0.5 milligrams per kilogram of bodyweight brought about hypotension which was not reducible by atropine.

The novel compounds I, possessing therapeutic action, are of lowtoxicity, and the ratio of activity to toxicity presents a satisfactorymargin. Thus, by way of example,

the DL of AU-2173 in mice is 222 milligrams per kilo-' gram of bodyweight when administered intraperitoneally, and 2600 milligrams perkilogram of body weight when administered orally. That of AU-2176 is158.3 milligrams per kilogram of body weight when intraperitoneallyadministered, and 956 milligrams per kilogam of body weight whenadministered orally.

Furthermore, the oral administration of AU-2176 in the form of itshydrochloride salt in a daily dosage of 60 milligrams per kilogram ofbody weight for 30 days in young rats does not prevent normal growth anddoes not modify the hematological constants.

Thus, as a result of their activity on the central nervous system, ournew compounds, those of formula I, are indicated as useful in thetreatment of psychic ailments and more particularly in depressivesyndromes of varied etiology, while the effects on the cardiovascularsystem justify their use in the treatment of cardiac arrythemias,normotopic or heterotopic.

7 liters content-may be prepared:

The new therapeutic agents may be administered orally or parenterally,the active agent being either in non-toxic salt form or in base form.

The compound of formula I may be prepared in the usual way foradministration with the usual vehicles and excipients suitable for thesemodes of administration. Thus, suitable pharmaceutical formulationsinclude tablets, dragees, gelatin capsules, solutions in ampoules andinjectable solutions which may be in ampoules. In these formulations theamount of active agent administered as a unit dose may vary from 5 tomilligrams, and there may be administered to the patient one or severalsuch doses daily. The average daily dose will ordinarily vary from 0.1milligram to 5 milligrams per kilogram of body weight of the patient.

There are given here below, by way of illustration, some examples ofthese formulations, as well as of the manner in which they may beprepared.

This formula may be converted into 100,000 tablets?" The hydrochloridesalt of AU2176, lactose and corn starch are incorporated in the potatostarch in the form of a 10% paste. The wet mass is graulatcd on a screenand dried at 45 C. The tablets are then prepared from the granulatedmass.

- Gms. AU-2'176 in the form of its hydrochloride salt 5,000 Lactose14,800 Magnesium stearate This preparation will yield 100,000 gelatincapsules each containing 200 milligrams of powder.

The mixture is thoroughly mixed and placed in capsules of appropriatesize.

C. INJECTABLE SOLUTION IN AMPOULES IN DOSAGES OF 10 MILLIGRAMS EACH Gms.

AU-2176 in the form of its hydrochloride salt 50 Water suitable for thepreparation of injectable solutions q.s.p. 50,000 mls.

From this solution 10,000 ampoules each of 5 milli- The AU-2176, in theform of its hydrochloride salt, is dissolved in warm water, filtered andplaced in ampoules of 5 milliliters content. They are then sterilized asby aseptic filtration or by-autoclaving.

We claim: 1. 5 (2 propyne-l-ylidene)dibenzo[a,d]-5H-cycloheptene.

2. 5 (2 propyne)-5-hydroxydibenzo[a,d]-5H-cyclof 'heptene.

References Cited UNITEDSTATES PATENTS 3,126,411 3/ 1964 Rey-Bellet etal. 260-570.8 TC 3,256,332 6/1966 Lassen 260570.8 TC 3,442,949 5/1969Wendler 260570.8 TC 3,723,420 3/1973 Dvolaitzky et al. 260240 TC FOREIGNPATENTS 1,017,696 1/1966 England 260570.8 TC

JOHN D. RANDOLPH, Primary Examiner U.S. Cl. X.R.

424-244, 248, 250, 267, 274, 330; 260239 B, 240 TC, 247.5 R, 268 TR,293.62, 326.81, 5 0.5 CA, 570.8 TC, 668 F

